The umami taste of amino acids (especially glutamate) and sweetness are the two appetitive taste qualities that are critical for our healthy attraction to protein and carbohydrate (energy) macronutrients. The likely evolutionary pressure for an appetitive protein taste system is our nutritional need: access to sources of dietary protein is essential for survival and kwashiorkor (dietary protein deficiency) is one of the leading causes of death in children in developing countries. Despite its importance in dietary selection, human umami taste remains one of the most poorly understood of the five taste qualities and its genetic and molecular determinants remain largely unknown. Three classes of glutamate receptors found within taste receptor cells have been associated with cell signaling in response to amino acids and ribonucleotides: (i) TAS1Rs, (ii) metabotropic-GluRs, and (iii) ionotropic-NMDA receptors. However, their respective roles in human umami taste perception are not known. The long term goal of the proposed work is to elucidate genetic and molecular mechanisms that are responsible for the human sensation of `umami' taste. The objectives of the proposed project are to clarify the roles of these three receptor classes, to identify other genes that may be involved with human umami taste perception, and to functionally test variant receptors associated with umami phenotypes. The specific Aims of this Proposal are: I. Identify variant genes and/or genome-wide loci associated with umami blindness. II. Characterize any umami perceptual phenotypes related to glutamate receptor SNPs. III. Define variant glutamate receptor stimulus-response functions in expression assays.PROJECT NARRATIVE This proposal will contribute to human health by identifying genes associated with human protein/amino acid taste (umami), which will subsequently guide nutritional intervention in protein malnourished people. Taste is significantly linked to nutrition, since our decision to accept or reject foods is ultimately based on our evaluation of food tastes. Hence, people who lose their sense of taste, such as radiotherapy patients, suffer nutrionally. Frequently, children in developing nations prefer foods with high levels of sugar, when available, over other food types. Too little protein in the diet (Kwashiorkor) is associated with one in every two children's deaths in the developing world. Since children with protein malnutrition prefer foods that have added free amino acids in experimental settings, a better understanding of amino acid taste mechanisms could guide the engineering of more appetitive foods that could help alleviate their malnutrition. Despite its importance in dietary selection, human umami taste remains one of the most poorly understood of the five taste qualities and its genetic and molecular determinants remain largely unknown. We will characterize how genes of candidate umami taste receptors and other genetic loci affect perceptual attributes of human amino acid taste through interdisciplinary studies that combine human perception, genetics, and molecular receptor functions.